Annual Meeting Proceedings Part 1 - American Society of Clinical ...

4573 General Poster Session (Board #1B), Sun, 8:00 AM-12:00 PM
Expression of MET and HGF in bladder cancer tumorigenesis and invasion.
Presenting Author: Randy F. Sweis, University of Michigan, Ann Arbor, MI
Background: The human MET gene encodes the hepatocyte growth factor
(HGF) tyrosine kinase receptor. Limited studies in human bladder cancer
have demonstrated that expression of MET protein is linked with disease
progression and survival. We hypothesized that the expression of both MET
and its ligand HGF are altered in bladder cancer. Methods: Expression of
MET and HGF in human bladder tissues was explored using Oncomine, an
online compendium of cancer transcriptome profiles. The largest relevant
dataset was identified and contained 157 samples (Sanchez-Carbayo, et al.
2006). Normalized and log2 transformed mRNA expression values for
Affymetrix U133 microarray probe sets corresponding to the genes of
interest were compiled and averaged for each gene. Mann-Whitney U
testing was used to compare means. Nominal and standard least squares
logistic regression was used to evaluate the predictive significance of, and
relevance of clinicopathologic variables on, gene expression. Statistical
analyses were carried out using JMP 9.0.2. Results: Expression of MET and
HGF was compared across subsets of normal bladder tissue (n�48),
superficial tumors (n�28), and invasive tumors (n � 81). Relative to
normal tissue, MET expression was greater in superficial (p � 0.0008) and
invasive tumors (p�0.0001). HGF expression was reduced in both invasive
and superficial tumors vs. normal tissue (both p� 0.0001), but was higher
in invasive vs. superficial tumors (p� 0.0007). In a logistic regression
model of tumor samples, both MET and HGF correlated with tumor invasion
(model p�0.0003). Interaction between MET and HGF was not significant
(p�0.55). Neither MET nor HGF expression was predicted by regression
using age, gender, grade, or nodal stage (p�0.16 and 0.27, respectively).
Conclusions: Decreased HGF expression and MET over-expression are
strongly associated with tumorigenesis and invasion in bladder cancer. The
reduction in HGF expression is blunted in invasive vs. superficial tumors,
suggesting a potential loss of negative feedback in more aggressive tumors.
Expression of both genes could not be predicted by modeling clinicopathologic
variables. MET signaling represents a potential therapeutic target in
bladder cancer.
4575 General Poster Session (Board #1D), Sun, 8:00 AM-12:00 PM
Defining a nine-biomarker panel for predicting bladder cancer outcome in
combination with smoking intensity: A report from the Los Angeles Cancer
Surveillance Program. Presenting Author: Anirban Pradip Mitra, University
of Southern California Keck School of Medicine and Norris Comprehensive
Cancer Center, Los Angeles, CA
Background: Urothelial carcinoma of the bladder (UCB) is a disease of
alterations in several cellular pathways. Routine molecular profiling studies
do not account for smoking, a well established risk factor for UCB, and its
influence on outcome. This study assessed the prognostic potential of a
multi-pathway protein panel across all UCB stages in a population-based
cohort after accounting for clinicopathologic factors and smoking history.
Methods: 212 UCB patients from the LA CSP, part of the NCI/SEER cancer
registry, were included. �Smoking intensity� analyzed biologic and molecular
impact of smoking by combining smoking status, duration of smoking
and number of cigarettes smoked daily into a composite covariate. Tumors
were profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, COX2, VEGF
and E-cadherin alterations by IHC. Univariate analyses and multivariable
modeling examined associations with outcome. Results: Median follow up
was 13.2 years. Age, pathologic stage, adjuvant therapy (all p� 0.001) and
surgical modality (p � 0.05) were associated with survival. Increasing
smoking intensity was associated with worse outcome (P � 0.001). Apaf-1
(p � 0.005), E-cadherin (p � 0.014) and p53 (p � 0.032) were
univariately prognostic; E-cadherin remained prognostic after multivariate
analysis (p � 0.04). Combined alterations in all 9 biomarkers were
prognostic by univariate (p � 0.001) and multivariate (p � 0.006)
analysis. A multivariate model that included all 9 biomarkers and smoking
intensity was more accurate in predicting prognosis than models comprising
of standard clinicopathologic covariates without (p � 0.001) or with (p
� 0.018) smoking intensity. Conclusions: The study confirms detrimental
effects of smoking on UCB prognosis. Apaf-1, E-cadherin and p53
individually predicted UCB survival. Increasing number of biomarker
alterations was significantly associated with worsening survival, although
markers contained in the panel were not necessarily prognostic individually.
Predictive value of the nine-biomarker panel with smoking intensity
was significantly higher than that of routine clinicopathologic parameters
alone.
Genitourinary Cancer
4574 General Poster Session (Board #1C), Sun, 8:00 AM-12:00 PM
Results of a phase II study of pralatrexate in patients with advanced/
metastatic relapsed transitional cell carcinoma of the urinary bladder.
Presenting Author: Yohann Loriot, Institut Gustave Roussy, Villejuif, France
Background: Antifolate agents have demonstrated activity in transitional
cell carcinoma (TCC), a disease with very poor outcomes in advanced
stages. Pralatrexate (FOLOTYN, Allos Therapeutics, Inc., Westminster,
CO), a folate analogue targeting dihydrofolate reductase, is designed for
enhanced uptake and accumulation in tumor cells. The objective of this
study was to examine the activity and safety of pralatrexate in patients (pts)
with advanced/metastatic TCC of the urinary bladder after failure of prior
chemotherapy. Methods: Pts with histologically confirmed TCC (�50% TCC
in tumor) received pralatrexate 190 mg/m² intravenously on days 1 and 15
of a 28-day cycle supplemented with vitamin B12 and folic acid. Included
pts had Eastern Cooperative Oncology Group performance status of 0–1,
measurable disease, and prior treatment with �1 platinum- and/or methotrexate-based
regimen in the recurrent/metastatic setting. Results: Thirty
pts were enrolled and treated. All pts received prior platinum-based
therapy, and 7 pts (23%) received methotrexate in a multidrug regimen.
One pt had a confirmed partial response (PR); 4 additional pts had
unconfirmed PRs. Twelve pts had stable disease. The median number of
cycles received was 2 (range, 1–24), and median time on treatment was 56
days (range, 1–714). The median progression-free survival (PFS) and
overall survival for all pts was 4.0 months (95% confidence interval [CI],
2.1–4.5) and 9.3 months (95% CI, 5.6–13.2), respectively. Eight pts
(27%) had PFS �6 months and 3 pts (10%) had PFS �12 months. Eight
pts (27%) underwent dose reductions, all due to mucositis. Six pts (20%)
discontinued the study due to treatment-related adverse events (AEs)—
mainly mucositis. The most frequent treatment-related AEs were stomatitis
(77%), asthenia (30%), vomiting (27%), and anemia, nausea, and
neutropenia (23% each). Conclusions: Pralatrexate showed evidence of
activity and durable disease control when used as a single agent in pts with
advanced bladder cancer, although the overall response rate was modest.
Further study of pralatrexate in this setting should focus on improving drug
delivery and evaluation of novel combination approaches.
4576 General Poster Session (Board #1E), Sun, 8:00 AM-12:00 PM
The impact of preoperative ASA score and serum albumin on early
complication and survival rate of patients undergoing radical cystectomy
for bladder cancer. Presenting Author: Hooman Djaladat, Institute of
Urology, University of Southern California, Los Angeles, CA
Background: American Society of Anesthesiologist Score (ASA-S) is used to
evaluate patient physical status before surgery. Serum albumin (Alb) is also
a marker of nutritional status. We evaluated the impact of preoperative
ASA-S and Alb on early complication rate and survival of patients who
underwent radical cystectomy for bladder cancer. Methods: 1964 patients
with primary bladder cancer underwent radical cystectomy between 1971
and 2008 at USC. Preoperative serum Alb and ASA-S were available in
1471 and 1140 patients respectively. Post cystectomy early complication
was defined as any surgery related/unrelated event leading to lengthening
hospital stay or re-admission within 90 days of surgery. Recurrence free
survival (RFS) and overall survival (OS) for these cohorts were reviewed
using a Kaplan-Meier and Cox proportional hazards models. Results: The
demographic data of patients based on their serum Alb and ASA-S is
presented in the Table. The median follow up was 12.4 years (0 - 36.6 yrs).
Low serum Alb (�3.4 g/dL) and high ASA-S (3 or 4) were associated with
higher early complication rate (43% vs. 33%, p� 0.03 and 40% vs. 28%,
p� 0.0001 respectively). In multivariable analysis, low serum Alb level was
an independent predictor of RFS (HR 1.35, 95% CI 1.00-1.81) and OS
(HR 1.62, 95% CI 1.29-2.04). High ASA-S was an independent predictor
of OS (HR 1.45, 95% CI 1.13-1.85), but not RFS. Conclusions: Preoperative
low serum Alb and high ASA-S are independently predictive of post
cystectomy decreased OS. Low serum Alb is also a risk factor for recurrence
after cystectomy. These parameters potentially could be used in nomograms
to predict post-cystectomy prognosis.
Demographic data in patients who underwent cystectomy for bladder
cancer based on preoperative serum Alb and ASA-S respectively.
Pts No Male sex
Alb< 3.4 137 92
(67%)
Alb> 3.4 1334 1062
(79%)
ASA�1, 2 400 320
(80%)
ASA�3, 4 740 574
(78%)
Median age
(range) LVI
74
(51-90)
67
(30-93)
60
(35-90)
69
(33-92)
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62
(45%)
373
(28%)
98
(25%)
226
(30%)
Multi
focality
46
(33%)
497
(37%)
150
(38%)
275
(37%)
High
grade
126
(92%)
1101
(82%)
317
(79%)
608
(82%)
295s
Stage
> pT3
87
(63%)
461
(35%)
116
(29%)
258
(35%)